The Cancer Biology Laboratory has for many years used the v-Ha-ras transgenic Tg.AC mouse model to study the molecular and biological events associated with skin tumor development. Early work in the laboratory demonstrated a potential link between papilloma development and ectopic expression of the ras transgene in hair follicle epidermal stem and progenitor cells. From this, we discovered that the hematopoietic stem cell marker CD34 is uniquely expressed on hair follicle bulge keratinocytes in mouse skin. CD34-expressing bulge cells have been demonstrated to be both slowly cycling and multipotent, identifying them as a stem and progenitor cell population. Because of the localization of CD34 on carcinogen target cells in the hair follicle, we tested the hypothesis that CD34 may have a dynamic function in skin tumor development. Using a CD34KO mouse line, we have shown that CD34 plays a role in stem cell activation and papillomagenesis using the two-stage model of skin tumorigenesis. [unreadable] Gene expression analysis of CD34+ keratinocytes revealed expression of the Deleted in Split Hand/Split Foot 1 (Dss1), which has subsequently been shown to have a growth regulatory role in the cell. We have determine that Dss1 mediates its growth regulation effects through direct binding with the Rpn3/S3 subunit of the 19S regulatory particle of the proteasome assembly, with important implications in binding of the proteasome to ubiquitinylated substrates and subsequent protein degradation. [unreadable] To understand key signaling pathways in tumor development, we generated p19ARFhetTgAChemi and p19ARFnullTgAChemi mice to explore the relationship between Ha-ras and p19ARF in skin tumor development. The p19ARFnullTgAChem mice unexpectedly developed tumors in the gastrointestinal tract that were subsequently revealed to be Gastrointestinal Stromal Tumors (GIST), which are the most common mesenchymal tumor of the gastrointestinal tract in humans. This model offers the unique opportunity to study GIST biology from the early preinvasive lesion to malignancy.